Nitroglycerin, also called glycerol trinitrate or GTN, is an active substance for the treatment of angina pectoris attacks. Among other things, it is used in emergencies when the medication should be fast acting.
The pharmaceutical agents used for this specific purpose, such as sublingual tablets or crunchable capsules, have disadvantages. A disadvantage, amongst others, is that after intake the active agent in these pharmaceutical agents must first be released and dispersed prior to being available for resorption in dissolved form. Furthermore, the loss of time needed to take the pharmaceutical agent out of a blister package can be critical during an acute angina attack.
To avoid the disadvantages of the described pharmaceutical forms, nitroglycerin-containing sprays have been developed. By spraying a dose of the active agent into the buccal area of the mouth, a direct and rapid dispersion of a solution of the active agent over as large a portion as possible of the oral mucosa, which absorbs the active agent nitroglycerin was to be achieved. In this way, a large area was to be reached, thereby accelerating absorption of the active agent.
The previously known nitroglycerin pharmaceutical solutions are characterized by high vapor pressure, solution properties, and an explosive nature which have limited their use and acceptance. Therefore, a desensitized active agent--supplementary agent mixture has to be used for safety reasons during the formulation of the pharmaceutical agent spray.
Based on its lipophilic characteristics, nitroglycerin is readily soluble in solvents such as ether, acetone, ethylacetate, benzol, chloroform and triglycerides. On the other hand, the solubility of nitroglycerin in hydrophilic solvents, such as water, is limited. The solubility of nitroglycerin in water amounts to merely about 1.1 mg/ml.
Because of the low solubility of nitroglycerin in water the solvents used in the customary spray formulations are lipophilic, i.e. oils or triglycerides. However, the lipophilic solvents prevent dispersion of the active agent nitroglycerin into the hydrophilic mucosa with the desired speed during acute angina pectoris attacks.
Previously, if it was desired to increase the availability of an active agent, the amount of the lipophilic solvent was reduced. However, the nitroglycerin surge duration, measurable via the maximum plasma nitroglycerin glycerin concentration (C.sub.max) and the time of the maximum concentration (t.sub.max), was only insignificantly affected.
It is reported that P.M. Dewland et al [Heart and Vessels, 7, 536-544 (1987)] obtained higher C.sub.max values (Table 1) for three nitroglycerin sprays, manufactured with lipophilic solutions, by decreasing the amount of the lipophilic formulation portions; however, the t.sub.max is not significantly different.
Another way to increase the availability of the active agent is described in the DE-A 32 46 081. That reference discloses increasing the propellant portion to 60-95% by weight of the formulation. The increased propellant portion effects a higher concentration of the active agents in non-volatile oily solvents. Furthermore, the active agent must first diffuse in the mucosa from the oily active agent solution. However, the surge of the active agent, which is important when the angina attack occurs, cannot be significantly shortened. Also, for reasons of increased environmental consciousness, it is undesirable to increase the amount of propellant, so this should be avoided.
A qualitatively significant improvement in treating an angina attack is not possible if lipophilic solvents are retained in the spray.
Another starting point for quickly dispersing the active agent in the hydrophilic mucosa, is the use of a solution with dissolving characteristics which are as small as possible for the active agent nitroglycerin. In this regard, it is necessary to take into consideration that the spray formulation solution or solution mixture desensitizes the active agent nitroglycerin sufficiently and also that the solution be technically easy to handle with respect to production requirement.
U.S. Pat. No. 3,155,574 describes a nitroglycerin spray formulation-for inhalation using a hydrophilic solution base containing the active agent nitroglycerin, 1,2-propanediol and ethanol free of water, but actual exemplified embodiments of the primary packaging means are missing. However, inhalation is rather detrimental to a patient during the occurrence of an angina attack since it is more difficult to carry out. More desirable are nitroglycerin-containing sprays in which the active agent is sufficiently absorbed through the oral mucosa, so that inhalation of the active agent is not necessary.
Investigations by H. Laufen et al, reported in Therapy Week, 34, 963-970 (1984) indicated that when a hydrophilic formulation, as compared to nitroglycerin-containing sprays using a lipophilic base, is used the amount of the active agent in the blood, as well as the amount of the absorbed substance, is faster and greater than when a lipophilic base is used. The authors report use of a pump spray for dosing the solution. We know from general experience that pump sprays presently do not meet the requirements for administering pharmaceutical agents so that the formulation or composition of Laufen et al having the described therapeutically beneficial effect cannot be converted into a useful pharmaceutical agent.
The EP-A 0 310 910 describes a nitroglycerin-containing spray formulation which, besides the active agent, contains only ethanol and water as a solvent and is adjusted to a pH value of 2.4 to 6.7. However, during evaporation of the ethanol the active agent in this formulation experiences a phase separation from the water and thus is not present in a desensitized form, even though desensitization actually is desirable for safety reasons.
The present state of technology with respect to sprays having a hydrophilic base, as compared to those having a lipophilic base, reveals shortcomings, such as an absorption of nitroglycerin in the valve component parts and a reduction of the dosage amount of the active agent nitroglycerin during each new or individual spray puff or shot.